The present invention relates to synthetic intermediates for production of compounds having thienopyridine skeleton and being useful for medicines, agricultural chemicals, and so forth, especially thienopyridine derivatives exhibiting gonadotropin releasing hormone (GnRH) antagonizing activity, and their production.
As a basic structure of a thienopyridine, 4,7-dihydro-4-oxo-thieno[2,3-b]pyridine of the formula: 
or thieno[2,3-b]pyridine of the formula:. 
is exemplified.
Thienopyridines are known to have antibacterial activities as well as other activities found recently such as angiotensine II antagonistic activities and GnRH antagonistic activities, due to which they are expected to be used widely in the fields of medicines and agricultural industries. Concerning the synthetic method for 5-acyl-4-hydroxythieno[2,3-b]pyridine derivative, one of such thienopyridines, there are examples reported on a direct synthesis of 5-acetyl-4-hydroxythieno[2,3-b]pyridine from 2-aminothiophene by a method called Gould-Jacobs method characterized by employing an ethoxymethylene compound of an active methylene compound as shown below [M. A. -Khan et al., J. Heterocyclic Chem., Vol. 14, p. 807 (1977)]: 
a synthesis from a corresponding acyl group-containing polysubstituted pyridine as shown below (F. A. Abu-Shanab et al., J. Chem. Soc. Perkin Trans. 1, 1994, page 1449): 
and a synthesis through functional group conversion in the 5-position of a 5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyridine derivative or a 5-cyano-substituted derivative thereof obtained by a conventional procedure as shown below [WO 95/28405 (JP-A-8-295693)]: 
wherein R51 represents hydrogen or a group through a carbon, nitrogen, oxygen or sulfur atom, R52 represents hydrogen or alkyl, R53 a hydrocarbon group, and R54 represents phenyl-alkylene which may be substituted.
In order to produce a thienopyridine derivative having a GnRH antagonistic effect, a compound having a nitrophenyl in the 2-position and a halogenomethyl in the 3-position is produced as an intermediate in WO 95/28405 (JP-A-8-295693). In the production of this compound, a nitro group is first introduced into the phenyl of the compound having a phenyl in the 2-position and a methyl in the 3-position and then the methyl in the 3-position is converted into a halogenomethyl.
Also in WO 95/28405 (JP-A-8-295693), a compound having an acid amide in the 5-position is produced from a compound having a carboxylic acid ester in the 5-position.
In the method by M. A. Khan et al. described above, the product is provided via an undesirable step such as the involvement of an organotin compound in an attempt to avoid the formation of an unstable 2-aminothiophene as an intermediate, while the method by F. A. Abu-Shanab et al. provides a O-ethylated product and involves a limitation in terms of the substituents on the thiophene ring, because of which the range of the application is limited.
On the other hand, the method for obtaining a 5-acyl form by the functionality conversion of a 5-ethoxycarbonyl-4-hydroxythieno[2,3-b]pyridine derivative or a 5-cyano-substituted derivative thereof which are obtained by a conventional method involves a less efficient multiple-stage synthesis. In the production of a GnRH antagonistic thienopyridine derivative employing this conventional method disclosed in WO 95/28405 (JP-A-8-295693) involves a large number of the production steps, which also make this method less efficient.
Accordingly, there has still been a desire to develop a method for producing a 5-acyl-4-hydroxythieno[2,3-b]pyridine skeleton conveniently and efficiently.
In the method disclosed in WO 95/28405 (JP-A-8-295693) which involves a conversion of the methyl in the 3-position of a compound having a nitrophenyl in the 2-position and the methyl in the 3-position into a halogenomethyl, carbon tetrachloride is employed as a solvent (see Example 6 in this publication). Since carbon tetrachloride has a high toxicity, an industrial or safety and sanitary consideration encourages to use a method employing no carbon tetrachloride. Nevertheless, no use of carbon tetrachloride results in a disadvantageous intermission of a brominating reaction.
In the method disclosed in WO 95/28405 (JP-A-8-295693), for producing a compound having an acid amide structure in the 5-position from a compound having a carboxylic acid ester in the 5-position, trimethylaluminum is used (see Example 50 in this publication). Since this trimethylaluminum is readily flashing and flammable, highly toxic and should be free from water, it should be handled with a great care. Industrially, a safe production method requiring no use of trimethylaluminum is desired.
We made an effort under the circumstance mentioned above and finally found that by halogenating the methyl in the 3-position of 4,7-dihydro-4-oxothieno[2,3-b]pyridine represented by the formula: 
having a phenyl in the 2-position and a methyl in the 3-position followed by introducing a nitro group into the phenyl in the 2-position of a resultant compound, a rapid halogenation in a solvent other than carbon tetrachloride, such as an easily-handled solvent such as ethyl acetate, under a gentle and convenient condition is possible in a halogenation process, and an easily-operable nitration by dissolving said halogenated compound in a solvent such as methanesulfonic acid followed by reacting with various nitrates in a nitration process is also possible.
It is also found that by producing a compound having an acid amide structure in the 5-position from a compound having a free carboxylate in the 5-position a target compound can be produced safely and conveniently in a high yield and a high purity without requiring the use of dangerous trimethylaluminum.
Also, the present inventors found out that a compound of the formula: 
or a salt thereof, is obtained in high yield by subjecting a compound of the formula: 
or a salt thereof to cyclization.
The inventors conducted further investigation based on this finding, and developed the present invention.
The present invention, therefore, relates to:
(1) a compound of the formula: 
wherein R11a represents hydrogen or halogen, and R41a represents C1-6 alkyl, C1-6 alkoxy or C6-10 aryl, with proviso that R41a is not ethoxy when R11a is hydrogen, or a salt thereof;
(2) a compound of the above (1) or a salt thereof, wherein R11a is hydrogen or bromo;
(3) a compound of the above (1) or a salt thereof, which is 7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-3-methyl-4-oxo-2-phenylthieno[2,3-b]pyridine;
(4) a compound of the above (1) or a salt thereof, which is 4 3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxo-2-phenylthieno[2,3-b]pyridine;
(5) a compound of the above (1) or a salt thereof, which is 3-bromomethyl-7-(2,6-difluorobenzyl)-4,7-dihydro-4-oxo-2-phenylthieno[2,3-b]pyridine-5-carboxylic acid ethyl ester;
(6) a process for producing a compound of the formula: 
wherein X represents halogen, R12a represents a divalent hydrocarbon group which may be substituted, R3a represents a hydrocarbon group which may be substituted, R4a represents a hydrocarbon group or a hydrocarbon-oxy group, and R22a represents a hydrocarbon group substituted by nitro, or a salt thereof, which comprises subjecting a compound of the formula: 
wherein R21a represents a hydrocarbon group and other symbols are as defined above, or a salt thereof to nitration;
(7) a process of the above (6), wherein R12a is methylene, R21a is phenyl, R22a is nitrophenyl, R3a is difluorophenyl-methyl, and R4a is isopropyl or ethoxy;
(8) a process for producing a compound of the formula: 
wherein X represents halogen, R12a represents a divalent hydrocarbon group, and R4a represents a hydrocarbon group or a hydrocarbon-oxy group, or a salt thereof, which comprises subjecting a compound of the formula: 
wherein R1a represents a hydrocarbon group which may be substituted and the other symbol is as defined above, or a salt thereof to halogenation;
(9) a process of the above (8), wherein the halogenation is carried out in the presence of methyl acetate;
(10) a process of the above (8), wherein X is bromo, R1a is methyl, R12a is methylene, and R4a is isopropyl or ethoxy;
(11) a process for producing a compound of the formula: 
wherein X represents halogen, R12a represents a divalent hydrocarbon group which may be substituted, R3a represents a hydrocarbon group which may be substituted, R4a represents a hydrocarbon group or a hydrocarbon-oxy group, and R22a represents a hydrocarbon group substituted by nitro, or a salt thereof, which comprises subjecting a compound of the formula: 
wherein R1a and R2a each represents a hydrocarbon group which may be substituted and other symbols are as defined above, or a salt thereof to halogenation to obtain a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof, and then subjecting the resultant compound to nitration;
(12) a process of the above (11), wherein R1a is methyl, R12a is methylene, R2a is phenyl, R22a is nitrophenyl, R3a is difluorophenyl-methyl, and R4a is isopropyl or ethoxy;
(13) a process for producing a compound of the formula: 
wherein R1a, R2a and R3a each represents a hydrocarbon group which may be substituted, and R5a and R6a each represents a hydrocarbon group, or a salt thereof, which comprises reacting compound of the formula: 
wherein each symbol is as defined above, or a salt thereof with a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof;
(14) a process of the above (13), wherein R1a is methyl which may be substituted by N-benzyl-N-methylamino, R2a is phenyl which may be substituted by isobutyrylamino, R3a is difluorophenyl-methyl, and R5a and R6a are methyl;
(15) a compound of the formula: 
wherein R11 represents C1-6 alkyl, R21 represents phenyl which may be substituted, or R11 and R21 form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R3 represents a hydrocarbon group which may be substituted, and R5 represents hydrogen or a hydrocarbon group, or a salt thereof;
(16) a compound of the above (15) or a salt thereof, wherein the substituent of the phenyl which may be substituted for R21 is isobutyrylamino or methoxy;
(17) a compound of the above (15) or a salt thereof, which is 4-hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine;
(18) a compound of the above (15) or a salt thereof, which is 4-hydroxy-5-isobutyryl-2-(4-isobutyrylaminophenyl)-3-methylthieno[2,3-b]pyridine;
(19) a process for producing a compound of the formula: 
wherein R1 and R2 each represents a hydrocarbon group which may be substituted, or R1 and R2 form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R3 represents a hydrocarbon group which may be substituted, and R5 represents hydrogen or a hydrocarbon group, or a salt thereof, which comprises subjecting a compound of the formula: 
wherein R4 represents a hydrocarbon group and other symbols are as defined above, or a salt thereof to cyclization;
(20) a process of the above (19), wherein R1 is methyl, R2 is phenyl which may be substituted by isobutyrylamino or methoxy, or R1 and R2 form, taken together with adjacent two carbon atoms, tetrahydrobenzene ring, R3 is methyl, isopropyl or phenyl, R4 is ethyl, and R5 is hydrogen;
(21) a compound of the formula: 
wherein R1 and R2 each represents a hydrocarbon group which may be substituted, or R1 and R2 form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R3 represents a hydrocarbon group which may be substituted, R4 represents a hydrocarbon group, and R5 represents hydrogen or a hydrocarbon group, or a salt thereof;
(22) a compound of the above (21) or a salt thereof, wherein R1 is methyl, R2 is phenyl which may be substituted by isobutyrylamino, methoxy or nitro, or R1 and R2 form, taken together with adjacent two carbon. atoms, tetrahydrobenzene ring, R3 is methyl, isopropyl or phenyl, R4 is ethyl, and R5 is hydrogen;
(23) a compound of the above (21) or a salt thereof, which is 4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]-5-phenylthiophene-3-carboxylic acid ethyl ester;
(24) a compound of the above (21) or a salt thereof, which is 5-(4-isobutyrylaminophenyl)-4-methyl-2-[(4-methyl-3-oxo-1-penten-1-yl)amino]thiophene-3-carboxylic acid ethyl ester;
(25) a process for producing a compound of -the formula: 
wherein R1 and R2 each represents a hydrocarbon group which may be substituted, or R1 and R2 form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R3 represents a hydrocarbon group which may be substituted, R4 represents a hydrocarbon group, and R5 represents hydrogen or a hydrocarbon group, or a salt thereof, which comprises reacting a compound of the formula: 
wherein each symbol is as defined above, or a salt thereof, with a compound of the formula: 
wherein R6 represents hydrogen, sodium, potassium or a hydrocarbon group and other symbols are as defined above, or a salt thereof;
(26) a process of the above (25), wherein R1 is methyl, R2 is phenyl which may be substituted by isobutyrylamino, methoxy or nitro,or R1 and R2 form, taken together with adjacent two carbon atoms, tetrahydrobenzene ring, R3 is methyl, isopropyl or phenyl, R4 is ethyl, and R5 is hydrogen;
(27) a process for producing a compound of the formula: 
wherein R1 and R2 each represents a hydrocarbon group which may be substituted, or R1 and R2 form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, R3 represents a hydrocarbon group which may be substituted, and R5 represents hydrogen or a hydrocarbon group, or a salt thereof, which comprises reacting a compound of the formula: 
wherein R4 is a hydrocarbon group, and other symbols are as defined above, or a salt thereof with a compound of the formula: 
wherein R6 represents hydrogen, sodium, potassium or a hydrocarbon group, and other symbols are as defined above, or a salt thereof, to obtain a compound of the formula: 
xe2x80x83wherein each symbol is as defined above, or a salt thereof, and then subjecting the resultant compound to cyclization;
(28) a process of the above (27), wherein R1 is methyl, R2 is phenyl which may be substituted by isobutyrylamino or methoxy, or R1 and R2 form, taken together with adjacent two carbon atoms, tetrahydrobenzene ring, R3 is methyl, isopropyl or phenyl, R4 is ethyl, and R5 is hydrogen;
(29) a compound of the formula: 
wherein R22 represents isobutyrylamino or methoxy, or a salt thereof;
(30) a compound of the above (29) or a salt thereof, which is 7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-isobutyrylaminophenyl)-3-methyl-4-oxothieno[2,3-b]pyridine;
(31) a process for producing a compound of the formula: 
wherein R23 represents phenyl which may be substituted by isobutyrylamino or methoxy, and R3 represents a hydrocarbon group which may be substituted, or a salt thereof, which comprises reacting a compound of the formula; 
wherein each symbol is as defined above, or a salt thereof, with a compound of the formula: 
wherein X represents halogen, or a salt thereof; and
(32) a dibasic acid salt of 7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-4-oxothieno[2,3-b]pyridine.
In the above formulae, halogen for R11a includes, for example, fluoro, chloro, bromo, iodo. Among others, bromo is especially preferred.
In the above formulae, C1-6 alkyl for R41a includes, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and so forth. Among others, C1-3 alkyl is preferred.
In the above formulae, C1-6 alkoxy for R41a includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, and so forth. Among others, C1-3 alkoxy is preferred.
In the above formulae, C6-10 aryl for R41a includes, for example, phenyl, 1-naphthyl, 2-naphthyl, and so forth. Among others, phenyl is preferred.
In the above formulae, halogen for X includes, for example, fluoro, chloro, bromo, iodo. Amongothers, bromo is especially preferred.
In the above formulae, preferred is a C1-20 hydrocarbon group as the hydrocarbon group of the hydrocarbon group which may be substituted for R1a, R2a or R3a, the hydrocarbon group for R4a, R5a or R6a, and the hydrocarbon group of the hydrocarbon-oxy for R4a.
The above C1-20 hydrocarbon group includes, for example, (1) C1-15 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc., preferably C1-6 alkyl, etc.), (2) C3-10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), (3) C2-10 alkenyl (e.g., vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl, 3-octenyl, etc.), (4) C2-10 alkynyl (e.g., ethynyl, propargyl, 2-propynyl, isopropynyl, 2-butynyl, 3-hexynyl, etc.), (5) C3-10 cycloalkenyl (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl), (6) C6-14 aryl (e.g., phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.), (7) C7-19 aralkyl (C6-14 aryl-C1-6 alkyl such as benzyl, phenethyl, benzhydryl, and trityl), and so forth.
The divalent hydrocarbon group of the divalent hydrocarbon group which may be substituted for R12a, includes preferably, for example, a divalent C1-20 hydrocarbon group such as (1) C1-15 alkylene (e.g., methylene, ethylene, n-propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene, preferably C1-6 alkylene, etc.), (2) C2-10 alkenylene (e.g., vinylene, allylene, 1-butenylene, 2-butenylene, butadienylene, isopropenylene, 2-methylallylene, hexatrienylene, 3-octenylene, etc., preferably-C2-6 alkenylene), (3) C2-10 alkynylene (e.g., ethynylene, propargylene, 2-propynylene, isopropynylene, 2-butynylene, 3-hexynylene, etc., preferably C2-6 alkynylene), and so forth.
The hydrocarbon group which may be substituted for R1a, R2a or R3a, and the divalent hydrocarbon group which may be substituted for R12a may have 1 to 6, preferably 1 to 5, more preferably 1 to 3, especially 1 or 2 substituents at possible positions of the hydrocarbon group.
The substituents of the hydrocarbon group which may be substituted for R1a, R2a or R3a, include, for example, (1) halogen (e.g., fluoro, chloro, bromo, and iodo), (2) nitro, (3) nitroso, (4) cyano or isocyano, (5) amino which may be substituted [e.g., an amino of the formula: xe2x80x94NR30aR31a wherein R30a and R31a each represents hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C2-10 alkenyl, C6-14 aryl, C7-19 aralkyl (C6-14 aryl-C1-5 alkyl, etc.), C1-10 acyl (C1-10 alkanoyl), C1-6 alkoxy-carbonyl, C1-6 alkylthio, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl or a heterocyclic group (a 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof, as mentioned below)], (6) hydroxy which may be substituted by substituent(s) selected from the group consisting of (i) C1-6 alkyl [this C1-6 alkyl may be substituted by halogen, hydroxy, C1-6 alkoxy, C2-10 alkenyl, C3-10 cycloalkyl, C1-3 alkylthio, C1-6 alkyl-carbonyl, carboxy, carbamoyl, C1-6 alkyl-carbamoyl, a heterocyclic group (a 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof, as mentioned below) or halogen], (ii) C1-4 acyl (C1-4 alkanoyl), (iii) C7-19 aralkyl (C6-14 aryl-C1-5 alkyl; this group may be substituted by halogen, C1-3 alkoxy or C1-4 alkyl), (iv) C6-14 aryl (this may be substituted by halogen), (v) C2-6 alkenyl, (vi) C3-7 cycloalkyl, (vii) C 1-3 alkoxy-carbonyl, (viii) mono- or C1-6 alkylamino, (ix) C2-6 alkenylamino, (x) C1-6 alkylcarbonyl, (xi) C3-6 cycloalkyl-oxycarbonyl, and (xii) trifluorosulfonyl, (7) a group of the formula: xe2x80x94S(O) n xe2x80x94R32a wherein n represents an integer of 0 to 2, and R32a represents hydrogen or a hydrocarbon group which may be substituted by substituents such as halogen, nitro, cyano, hydroxy, oxo, thioxo, carboxy, cyano-C6-14 aryl, halogeno-C6-14 aryl, etc.; in this hydrocarbon group, C1-20 hydrocarbon group is preferred, especially, C1-6 alkyl, C6-14 aryl, and C7-19 aralkyl (C6-14 aryl-C1-5 alkyl) are preferred, (8) carbamoyl which may be substituted (the substituents of this carbamoyl include, for example, mono- or di-C1-6 alkyl, preferably mono- or di-C1-3 alkyl, etc.), (9) a group through carbonyl [e.g., a group of the formula: xe2x80x94COxe2x80x94R33a wherein R33a represents (i) hydrogen, (ii) hydroxy, (iii) C1-6 alkyl, (iv) C1-6 alkoxy (this alkoxy may be substituted by C6-14 aryl which may be substituted by halogen or nitro, etc.), (v) C3-6 cycloalkyl, (vi) C6-14 aryl, (vii) C7-19 aralkyl (C6-14 aryl-C1-6 alkyl), (viii) amino which may be substituted (e.g. the above amino) or (ix) a heterocyclic group (a 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof, as mentioned below)], (10) a 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof, as mentioned below, (this heterocyclic group may be substituted by (i) halogen, (ii) C1-4 alkyl, (iii) C1-3 alkoxy, (iv) C1-4 alkylthio, or (v) phenoxy which may be substituted by halogen), (11) sulfo, (12) C6-14 aryl (e.g., phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.; this aryl may be substituted by 1 to 4 substituents selected from the group consisting of (a) hydroxy, (b) amino, (c) mono- or di-C1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), (d) C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, hexyloxy, etc.) and (e) halogen (fluoro, chloro, bromo and iodo ), (13) aryloxy [this aryl is same as the above (12)], (14) C3-7 cycloalkyl, (15) C1-6 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, propylenedioxy, etc.), (16) oxo, (17) thioxo, (18) C3-4 alkynyl (e.g., propargyl, 2-butynyl, etc.), (19) C3-10cycloalkyl, (20) C2-10 alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, butadienyl, hexatrienyl, 3-octenyl, etc.; C2-6 alkenyl is preferred.), (21) C7-19 aralkyl (C6-14 aryl-C1-6 alkyl), (22) amidino, (23) azido, and so forth.
The substituents of the above-mentioned hydrocarbon group which may be substituted, may further have 1 to 3, preferably 1 or 2 substituents at possible positions. Said substituents, which the substituents may further have, include, for example, 1 to 4, preferably 1 or 2 substituents selected from the group consisting of (1) hydroxy, (2) amino, (3) mono- or di-C1-4 alkylamino (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino etc.), (4) C1-4 alkoxy, preferably C1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), (5) halogen (fluoro, chloro, bromo, andiodo), and nitro, and so forth.
When the hydrocarbon group is cycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl or aralkyl, this hydrocarbon group may be substituted by 1 to 3 C1-6 alkyl, preferably C1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), and this C1-6 alkyl may be further substituted by 1 to 3 hydroxy, oxo, C1-3 alkoxy (e.g., methoxy, ethoxy, ethoxy, n-propoxy, isopropoxy etc.), C1-3 alkylthio, halogen, and carbamoyl, etc.
The substituted C1-6 alkyl includes formyl (methyl substituted by an oxo), carboxy (methyl substituted by an oxo and a hydroxy), C1-6 alkoxycarbonyl (methyl substituted by an oxo and an alkoxy) (e.g., C1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), hydroxy-C1-6 alkyl (e.g., hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl, etc.), C1-3 alkoxy-C1-6 alkyl(e.g., methoxymethyl, ethoxymethyl, ethoxybutyl, propoxymethyl, prbpoxyhexyl, etc.), and so forth.
The number of the above substituents is 1 to 6, preferably 1 to 5, more preferably 1 to 3, especially 1 or 2. The number of the substituents which substituents may further have, is 1 to 3, preferably 1 to 2.
In the definitions of the above-mentioned groups, C1-10 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. Among others, preferred is C1-6 alkyl, and more preferred is C1-4 alkyl or C1-3 alkyl. The C1-6 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. The C1-4 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. The C1-3 alkyl includes, for example, methyl, ethyl, n-propyl, and isopropyl.
In the definitions of the above-mentioned groups, as cycloalkyl preferred is C3-10 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc. Among others, C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.), and C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) are preferred.
In the definitions of the above-mentioned groups, C2-10 alkenyl includes, for example, vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl, 3-octenyl, etc. Among others, preferred is C2-6 alkenyl (e.g., vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl etc.).
In the definitions of the above-mentioned groups, C6-14 aryl includes, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.
In the definitions of the above-mentioned groups, C7-19 aralkyl includes, for example, C6-14 aryl-C1-5 alkyl such as benzyl, phenethyl-, benzhydryl, and trityl.
In the definitions of the above-mentioned groups, C1-6 alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, etc. Among others, C1-4alkoxy or C1-3 alkoxy (e.g., methoxy, ethoxy, n-propoxy, and isopropoxy) is preferred.
In the definitions of the above-mentioned groups, C1-10 acyl includes, for example, C1-10 alkanoyl (e.g., formyl, acetyl, propynyl, butyryl, isobutyryl, valeryl, andhexanoyl). Amongo thers, preferred is C1-4 acyl [e.g., C1-4 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, etc.)].
In the definitions of the above-mentioned groups, the heterocyclic group includes, for example, a 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof.
The examples of the above heterocyclic group include (1) a 5-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms in addition to carbon atoms, such as 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-,4- or 5-thiazolyl, 3-,4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, succinimido, etc., (2) a 6-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms in addition to carbon atoms, such as 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazinyl, triazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, 3- or 4-pyridazinyl, etc., (3) a bi- or tri-cyclic condensed heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms in addition to carbon atoms, such as benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo[1,5-b]pyridazinyl, triazolo[4,5-b]pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthylizinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, cromanyl, banzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalimido, etc.
Preferable examples of the above heterocyclic group include imidazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,4-thiazinyl, imidazolinyl, succinimido, phthalimido, etc.
Preferred examples of the substituents of the hydrocarbon group which may be substituted for R1a include (1) nitro, (2) amino whichmay be substituted by C1-10 alkyl, C1-10 acyl (C1-10 alkanoyl) or C1-6 alkoxy-carbonyl, etc., (3) hydroxy which may be substituted by C1-6 alkyl, C1-4 acyl (C1-4 alkanoyl), C1-3 alkoxy-carbonyl, C1-6 alkylcarbonyl, C3-6 cycloalkyl-oxycarbonyl or trifluorosulfonyl, etc., (4) a group of the formula: xe2x80x94S(O) n xe2x80x94R32a wherein n represents an integer of 0 to 2, and R32a represents hydrogen or a C1-10 hydrocarbon group (preferably C1-6 alkyl), (5) succinimido, (6) phthalimido, and so forth.
R1a preferably is (1) a C1-20 hydrocarbon group (preferably C1-6 alkyl), and (2) a C1-20 hydrocarbon group (preferably C1-6 alkyl) substituted by (i) amino which may be substituted by C1-1 alkyl, C1-10 acyl (C1-10 alkanoyl) or C1-6 alkoxy-carbonyl, (ii) succinimido or (iii) phthalimido. More preferably, R1a is (1) C1-6 alkyl, and (2) Nxe2x80x94C7-19 aralkyl-Nxe2x80x94C1-6 alkylamino-C1-6 alkyl (Nxe2x80x94C6-14 aryl-C1-6 alkyl-Nxe2x80x94C1-6 alkylamino-C1-6 alkyl), etc.
Preferred examples of the substituents of the hydrocarbon group which may be substituted for R2a include (1) nitro, (2) halogen, (3) amino which may be substituted by C1-10 acyl (C1-10 alkanoy) or C1-6 alkoxy-carbonyl, (4) hydroxy which may be substituted by C1-6 alkyl, C1-4 acyl (C1-4 alkanoyl), C1-3 alkoxy-carbonyl, C1-6 alkylcarbonyl, C3-6 cycloalkyl-oxycarbonyl or trifluorosulfonyl, (5) a group of the formula: xe2x80x94S(O) n xe2x80x94R32a wherein n represents an integer of 0 to 2, and R32a represents hydrogen or a C1-6 hydrocarbon group which may be substituted (preferably C1-6 aryl), (6) carbamoyl, (7) a group through carbonyl (e.g., C1-6 alkoxy-carbonyl, etc.), (8) succinimido, (9) phthalimido, and so forth.
R2a preferably is (1) a C1-20 hydrocarbon group (preferably C1-6 alkyl or C6-10 aryl), and (2) a C1-20 hydrocarbon group (preferably C1-6 alkyl or C6-10 aryl, more preferably C6-10 aryl) substituted by (i) amino which may be substituted by C1-10 acyl (C1-10 alkanoyl) or C1-6 alkoxy-carbonyl, (ii) hydroxy which may be substituted by C1-6 alkyl, C1-4 acyl (C1-4 alkanoyl), C1-3 alkoxy-carbonyl, C1-6 alkylcarbonyl or C3-6 cycloalkyl-oxycarbonyl, etc., (iii) succinimido or (iv) phthalimido. More preferably, R2a is (1) C6-14 aryl, (2) C1-8 alkanoylamino-C6-14 aryl, (3) C2-10 alkenyl-C1-6 alkoxy-C6-14 aryl, and so forth.
Preferred examples of the substituents of the hydrocarbon group which may be substituted for R3a include (1) nitro, (2) halogen, (3) amino which may be substituted, (4) hydroxy which may be substituted, (5) a group of the formula: xe2x80x94S(O) n xe2x80x94R32a wherein n represents an integer of 0 to 2, and R32a represents hydrogen or a C1-20 hydrocarbon group which may be substituted (preferably C1-6 alkyl), (6) carbamoyl which may be substituted, (7) a group through carbonyl (e.g., C1-6 alkoxy-carbonyl, etc.), and so forth.
Especially R3a preferably is, phenyl-C1-3 alkyl which may be substituted by halogen.
Preferred examples of the divalent hydrocarbon group which may be substituted for R12a include C1-6 alkylene. More preferred is methylene or ethylene.
Preferred examples of the hydrocarbon group for R4a or the hydrocarbon group of the hydrocarbon-oxy for R4a include C1-6 alkyl.
Preferred examples of the hydrocarbon group of the hydrocarbon group substituted by nitro for R22a include C1-6 alkyl.
Preferred examples of the hydrocarbon group for R5a or R6a include C1-6 alkyl.
R11a preferably is hydrogen or halogen (preferably bromo, etc.).
R41a preferably is C1-6 alkyl, C1-6 alkoxy, and phenyl. More preferred is C1-3 alkyl, ethoxy, phenyl, and so forth.
The following are processes of the present invention.
1. Halogenation in the present invention is carried out by reacting a material compound of the formula: 
wherein each symbols is as defined above, with a halogenating reagent to obtain a compound of the formula: 
wherein each symbols is as defined above.
The halogenating reagent includes N-halosuccinimide (e.g., N-bromosuccinimide, N-bromophthalimide, 1,3-dibromo-5,5-dimethylhydantoin), etc.
In this reaction, a radical initiator is advantageously used. The radical initiator includes, for example, 2,2xe2x80x2-azobisisobutyronitrile, benzoyl peroxide, 2,2xe2x80x2-azobis(2,4-dimethylvaleronitrile), and so forth.
The amount of the halogenating reagent to be used is about 1 to 1.5 mol, preferably about 1 to 1.2 mol relative to one mol of the material compound. The amount of the radical initiator to be used is about 0 to 0.5 mol, preferably 0.01 to 0.1 mol relative to one mol of the material compound.
In this reaction, a solvent is advantageously used. There is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Among others, preferably used are hydrocarbons (e.g., n-hexane, benzene, toluene, xylene, etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), and mixtures of those solvents.
The reaction time is advantageously from about 10 minutes to 5 hours, preferably from 1 to 3 hours. The reaction temperature is selected according to boiling point of the solvent that can be used in the reaction, for example, about 35xc2x0 C. to reflux temperature, preferably about 70xc2x0 C. to reflux temperature, more preferably about 70 to 80xc2x0 C. When methyl acetate is used, the reaction temperature is about 40xc2x0 C. to reflux temperature, preferably about 50 to 60xc2x0 C. When ethyl acetate is used, the reaction temperature is, for example, about 40xc2x0 C. to reflux temperature, preferably about 70xc2x0 C. to reflux temperature, more preferably bout 70 to 80xc2x0 C.
2. Nitration in the present invention is carried out by subjecting a material compound of the formula: 
wherein each symbol is as defined above, to nitration to obtain a compound of the formula: 
wherein each symbol is as defined above.
Said nitration is carried out according to an ordinary nitration method of aromatic compound. In this reaction, as a nitrating agent, (1) nitric acid, alkali metal of nitric acid (e.g., sodium nitrate, potassium nitrate, etc.) or ammonium salt of nitric acid (e.g., ammonium nitrate, etc.), or mixture with a strong acid is added. As for said strong acid, any acid may be used as far as it can generate nitronium ion from nitric acid. Among them, sulfuric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid, which have a high solubility against organic compound, are preferable and used as solvents at the same time.
At addition, it is preferable to drop said nitrating agent comprising 1 mole of nitric acid or nitrate to said strong acid solution of 1 mole of a material compound under said temperature.
This reaction may be carried out without a solvent or in the presence of a solvent. When a solvent is used, the solvent includes, for example, ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), sulfoxides (e.g., dimethylsulfoxide, etc.), amides (N,N-dimethylformamide, N,N-dimethylacetamide, etc.), esters (e.g., ethyl acetate, etc.), carboxylic acids (e.g., acetic acid, propionic acid), dimethoxyethane, etc., and mixtures of those solvents.
The reaction temperature is about xe2x88x9240 to 40xc2x0 C., preferably about 0 to 20xc2x0 C. The reaction time is about 10 minutes to 10 hours, preferably 1 to 2 hours.
3. The reaction of converting a carboxylic acid derivative to a N-substituted amide derivative, of the present invention is carried out by reacting a material compound of the formula: 
wherein each symbol is as defined above, with a N,O-dihydrocarbonhydroxylamine derivative of the formula: 
wherein each symbol is as defined above, or salt thereof, to obtain a compound of the formula: 
wherein each symbol is as defined above.
In this reaction, the amount of the N,O-dihydrocarbonhydroxylamine derivative or its salt is about 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to one mol of the material compound or its salt.
To this reaction system, advantageously added are about 1 to 5 equivalents, preferably about 1 to 3 equivalents of amines (e.g., triethylamine), about 1 to 5 equivalents, preferably about 1 to 3 equivalents of 1-hydroxybenzotriazole (HOBT), and about 1 to 5 equivalents, preferably 2 to 3 equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC).
This reaction is usually carried out in a solvent that does not interfere with the reaction. Such solvents include, for example, ethers (e.g., dioxane, tetrahydrofuran, 1,2-dimethoxyethane, etc.), ketones (e.g., acetone, etc.), nitrites (e.g., acetonitrile, etc.), amides (e.g., dimethylformamide, dimethylacetamide, etc.), dimethylsulfoxide, sulfolane, etc. and mixtures of those solvents.
This reaction is carried out at about 0 to 100xc2x0 C., preferably about 50 to 60xc2x0 C., for about 1 to 10 hours, preferably about 5 to 7 hours.
The material carboxylic acid derivative is obtained by for example, subjecting a compound of the formula: 
wherein R41a represents a hydrocarbon group and the other symbols are as defined above, which is disclosed in JP-A-8-295693 (WO 95/28405), to hydrolysis.
The hydrolysis is carried out by adding an acid (e.g., hydrochloric acid, sulfuric acid, etc.) or an alkali (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) to the reaction followed by stirring.
The solvents to be used include, for example, water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, etc.), tetrahydrofuran, acetone, acetonitrile, 1,2-dimethoxyethane , dioxane, etc.), and so forth. The reaction temperature is usually about 0 to 100xc2x0 C., preferably about 50 to 80xc2x0 C. The reaction time is preferably about 0.5 to 10 hours, preferably, about 1 to 4 hours.
4. The reaction of converting the resultant acid amide derivative as mentioned above to a ketone derivative, is carried out by reacting a material compound of the formula: 
wherein each symbol is as defined above, or a salt thereof with Grignard reagent [e.g., isopropyl magnesium chloride (2M-THF solution), isopropyl magnesium bromide, etc.] to obtain a material compound of the formula: 
wherein R42a represents a hydrocarbon group and other symbols are as defined above, or a salt thereof.
The amount of the Grignard reagent is about 1 to 10 equivalents, preferably about 2 to 4 equivalents relative to one mol of the material compound or a salt thereof.
This reaction may be carried out in the presence of a solvent, which can be used unless the reaction is interfered with. The solvent includes, for example, the same ones used in the above reaction for obtaining an acid amide derivative.
The reaction temperature is about xe2x88x9210 to 0xc2x0 C., preferably about xe2x88x925 to 0xc2x0 C. The reaction time is about 30 minutes to 5 hours, preferably about 40 to 50 minutes.
Salts of compounds used in these reactions and salts of compounds obtained in these reactions (hereinafter, referred to as xe2x80x9ccompound of the present inventionxe2x80x9d) are preferably physiologically acceptable acid addition salts. Such salts include, for example, salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.), saltswithorganic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.), and so forth. For example, when a compound of the present invention has an acidic group such as carboxylic acid, it may form a physiologically acceptable salt with an inorganic base (e.g., alkali metals or alkaline earth metals such as sodium, potassium, calcium and magnesium, ammonia, etc.) or an organic base (e.g., tri-C1-3 alkylamine such as triethylamine, etc.). The compound in free form can be converted to a salt and the one in salt form can be converted to a free form by per se known By methods or analogous thereto.
When the compound has a double bond, and there exist stereoisomers of Z- or E-form, Z-form, E-form and their mixture may be used.
When the compound has a chiral carbon atom, and there exist stereoisomers of R- or S-form, R-form, S-form and their mixture are within the scope of the present invention.
When the compound of the present invention or a salt thereof is an optically active compound, it can be resolved into the d- and l-forms by the conventional optical resolution techniques.
Thus obtained compounds or salt thereof may be isolated and purified by ordinary means of separation such as solvent extraction, concentration under reduced pressure, crystallization, recrystallization, distillation chromatography, and the like.
The compound obtained in the present invention or a salt thereof can be submitted to the next reaction either as the .reaction mixture or after partial purification.
The compound obtained in the present invention or a salt thereof is used for production of thienopyridine derivatives being useful as GnRH antagonists, according to the methods described in, for example, JP-A-8-295693 (WO 95/28405) or analogous methods thereto.
Therefore, the compound obtained in the present invention or a salt thereof can be used as synthetic intermediates for thienopyridine derivatives being useful as GnRH antagonists, which is described in, for example, JP-A-8-295693 (WO 95/28405).
Material compounds and salts thereof used in methods of the present invention can be produced, for example, by the methods described in WO 95/28405 (JP-A-8-295693) or analogous methods thereto.
In the above formulae, C1-6 alkyl for R11 includes, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., preferably methyl, ethyl, n-isopropyl, more preferably methyl.
In the above formulae, the 5- to 7-membered ring of the xe2x80x9c5- to 7-membered ring which may be substitutedxe2x80x9d which R11 and R21 form, taken together with adjacent two carbon atoms, and the 5- to 7-membered ring of the xe2x80x9c5- to 7-membered ring which may be substitutedxe2x80x9d which R1 and R1 form, taken together with adjacent two carbon atoms include a 5- to 7-membered ring which may contain 1 to 4 nitrogen atoms, sulfur atoms and/or oxygen atoms. Such examples are
(1) a ring of the formula: 
wherein R7 represents xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94CH2xe2x80x94R8xe2x80x94CH2xe2x80x94, xe2x80x94R8xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94R8xe2x80x94, xe2x80x94CH2xe2x80x94R8xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94R8xe2x80x94CH2xe2x80x94, xe2x80x94R8xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94R8xe2x80x94, xe2x80x94CH2xe2x80x94R8xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94R8xe2x80x94CH2xe2x80x94, xe2x80x94R8xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94R8xe2x80x94 wherein R8 represents (i) xe2x80x94NHxe2x80x94, (ii) xe2x80x94S(O) m xe2x80x94 wherein m represents an integer of 0 to 2, or (iii) xe2x80x94Oxe2x80x94,
(2) a 5-membered heterocycle containing 1 to 4 hetero atoms selected form oxygen atom, sulfur atom, nitrogen atom, etc., in addition to carbon atoms, such as thiophene, furan, oxazole, thiazole, pyrazole, imidazole, isoxazole, isothiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, 1,2,3-triazole, etc., and
(3) a 6-membered heterocycle containing 1 to 4 hetero atoms selected form oxygen atom, sulfur atom, nitrogen atom, etc., in addition to carbon atoms, such as pyridine, pyridazine, pyrimidine, triazine, pyrrolidine, pyran, pyrazine, etc.
Substituents which the 5- to 7-membered ring may have include halogen, C1-6 alkyl, C1-4 alkoxy, nitro, oxo, thioxo, alkylthio, cyano, C1-6 alkylcarbonyl, C1-4 alkoxycarbonyl, carbamoyl, mono-C1-6 alkylcarbamoyl, di-C1-6 alkylcarbamoyl, C1-10 acylamino (e.g., C1-10 alkanoylamino, etc.), di-C1-6 alkylamino, C6-14 aryl, C6-14 aryloxy, heterocyclic group (the above-mentioned xe2x80x9c5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereofxe2x80x9d), and so forth.
The above 5- to 7-membered ring may have 1 to 3 substituents above-mentioned at possible positions.
In the above formulae, as the hydrocarbon group of the hydrocarbon group which may be substituted for R1, R2 or R3, and as the hydrocarbon group for R4, R5 or R6, preferred is a C1-20 hydrocarbon group.
The C1-20 hydrocarbon group includes, for example, (1) C1-15 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc.), (2) C3-10 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), (3) C2-10 alkenyl (e.g., vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl, 3-octenyl, etc.), (4) C2-10 alkynyl (e.g., ethynyl, propargyl, 2-propynyl, isopropynyl, 2-butynyl, 3-hexynyl, etc.), (5) C3-10 cycloalkenyl (e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl), (6) C6-14 aryl (e.g., phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.), (7) C7-19 aralkyl (e.g., C6-14 aryl-C1-5 alkyl such as benzyl, phenethyl, benzhydryl, trityl, etc.), and the like.
Substituents of the hydrocarbon group which may be substituted for R1, R2 or R3 include, for example, (1) halogen (e.g.,fluoro,chloro,bromo,andiodo), (2)nitro, (3)nitroso, (4) cyano or isocyano, (5) substituted amino [e.g., a substituted amino of the formula: xe2x80x94NR30R31 wherein R30 and R31 each is hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C2-10 alkenyl, C6-14 aryl, C7-19 aralkyl (C6-14 aryl-C1-6 alkyl etc.), C1-10 acyl (C1-10 alkanoyl, preferably C1-4 alkanoyl ), C1-6 alkoxy-carbonyl, a group of the formula: xe2x80x94S(O)P-R32 wherein p represents 1 or 2, and R32 represents C1-6 alkyl,C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, or heterocyclic group (the above-mentioned 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof); provided that R30 and R31 are not hydrogen at the same time], (6) hydroxy which may be substituted by (i) C1-6 alkyl [this C1-6 alkyl may be substituted by halogen, C1-6 alkoxy, C2-10 alkenyl, C3-10 cycloalkyl, C1-3 alkylthio, oxy-C1-3 alkoxy, C1-6 alkyl-carbonyl, carbamoyl, C1-6 alkyl-carbamoyl, heterocyclic group (the above-mentioned 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof) or halogen], (ii) C1-4 acyl, (iii) C7-19 aralkyl (C6-14 aryl-C1-5 alkyl; this C7-19 aralkyl may be substituted by halogen, C1-3 alkoxy or C1-4 alkyl), (iv) C6-14 aryl (this C6-14 aryl may be substituted by halogen), (v) C2-6 alkenyl, (vi) C3-7 cycloalkyl, (vii) C1-3 alkoxy-carbonyl, (viii) di-C1-6 alkylaminocarbonyl, (ix) C1-3 alkoxy-carbonyl, (x) C1-6 alkylcarbonyl, (xi) C3-6 cycloalkyl-oxycarbonyl and (xii) C1-6 alkylsulfonyl or C6-14 arylsulfonyl each of which may be substituted by halogen, (7) a group of the formula: xe2x80x94S(O) n xe2x80x94R33 wherein n represents an integer of 0 to 2, and R33 represents hydrogen or a hydrocarbon group which may be substituted by substituent(s) (e.g., halogen, nitro, cyano, oxo, thioxo, cyano-C6-14 aryl, halogeno-C6-14 aryl etc.); the hydrocarbon group includes C1-20 hydrocarbon group, preferably C1-6 alkyl, C6-14 aryl, C7-19 aralkyl (C6-14 aryl-C1-6 alkyl), (8) carbamoyl which may be substituted (such substituent(s) includes, for example, mono- or di-C1-6 alkyl, preferably mono- or di-C1-3 alkyl, etc.), (9) a group through carbonyl [e.g., a group of the formula: xe2x80x94COxe2x80x94R34 wherein R34 represents (i) hydrogen, (ii) C1-6 alkyl, (iii) C1-6 alkoxy (this alkoxy may be substituted by C6-14 aryl which may be substituted by halogen or nitro, etc.), (v) C3-6 cycloalkyl, (vi) C6-14 aryl, (vii) C7-19 aralkyl (C6-14 aryl-C1-6 alkyl) or (viii) heterocyclic group (the above-mentioned 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof)], (10) heterocyclic group (the above-mentioned 5- to 8-membered saturated or unsaturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, or a condensed heterocyclic group thereof); this heterocyclic group may be substituted by (i) halogen, (ii) C1-4 alkyl, (iii) C1-3 alkoxy, (iv) C1-4 alkylthio or (v) phenoxy which may be substituted by halogen, (11) C6-14 aryl [e.g., phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.; this aryl may be substituted by 1 to 4 substituents selected form the group consisting of (a) C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, hexyloxy, etc.), (b) halogen (fluoro, chloro, bromo, and iodo) and (c)di-C1-4 alkylamino (e.g., dimethylamino, diethylamino etc.) etc.], (12) C6-14 aryloxy [this C6-14 aryl is as same as the above (11)], (13) C3-7 cycloalkyl, (14) C1-6 alkylenedioxy(e.g., methylenedioxy, ethylenedioxy, propylenedioxy, 2,2-dimethylenedioxy etc.), (15) oxo, (16) thioxo, (17) C3-4 alkynyl (e.g., propargyl, 2-butynyl, etc.), (18) C3-10 cycloalkyl, (19) C2-10 alkenyl (e.g., vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, butadienyl, hexatrienyl, 3-octenyl etc., preferably C2-6 alkenyl), (20) C7-19 aralkyl, (21) azido, and so forth.
The substituents of the above-mentioned hydrocarbon group which may be substituted, may further have 1 to 3, preferably 1 or 2 substituents at possible positions. Said substituents, which the substituents may further have, include, for example, 1 to 4, preferably 1 or 2 substituents selected from the group consisting of C1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), halogen (fluoro, chloro, bromo and iodo), nitro and di-C1-4 alkylamino (e.g., dimethylamino, diethylamino, etc.), etc.
When the hydrocarbon group is cycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl or aralkyl, this hydrocarbon group maybe substituted 1 to 3 C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, etc.), and this C1-6 alkyl may be further substituted by 1 to 3 oxo, C1,3 alkoxy (e.g., methoxy, ethoxy, ethoxy, n-propoxy, isopropoxy etc.) C1-3 alkylthio, halogen, and carbamoyl, etc.
The substituted C1-6 alkyl includes, formyl (methyl substituted by an oxo), C1-6 alkoxycarbonyl (methyl substituted by an oxo and an alkoxy) (e.g., C1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), C1-3 alkoxy-C1-6 alkyl (e.g., methoxymethyl, ethoxymethyl, ethoxybutyl, propoxymethyl, propoxyhexyl, etc.), and so forth.
The number of the above substituents is 1 to 6, preferably 1 to 5, more preferably 1 to 3, especially 1 or 2. The number of the substituents which substituents may further have, is 1 to 3, preferably 1 to 2.
In the definitions of the above-mentioned groups, C1-10 alkyl includes, for example, methyl, ethyl,-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., preferably C1-6 alkyl, more preferably C1-4 alkyl or C1-3 alkyl. The C1-6 alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl,etc. The C1-4 alkyl includes,for example,methyl,ethyl, n-propyl. isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. The C1-3 alkyl includes, for example, methyl, ethyl, n-propyl, and isopropyl.
In the definitions of the above-mentioned groups, C3-10 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., preferably C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), more preferably C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.).
In the definitions of the above-mentioned groups, C2-10 alkenyl includes, for example, vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl, 2-methylallyl hexatrienyl, 3-octenyl, etc., preferably C2-alkenyl (e.g., vinyl, allyl, 1-butenyl, 2-butenyl, butadienyl, isopropenyl, 2-methylallyl, hexatrienyl, etc.).
In the definitions of the above-mentioned groups, C6-14 aryl includes, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc. Preferred is C6-10 aryl.
In the definitions of the above-mentioned groups, C7-19 aralkyl includes, for example, benyl, phenethyl, benzhydryl, trityl, etc.
In the definitions of the above-mentioned groups, C1-6 alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy-butoxy, etc. Among others preferred is C1-4 alkoxy or C1-3 alkoxy (e.g., methoxy, ethoxy, n-propoxy, and isopropoxy).
In the definitions of the above-mentioned groups, C1-10 acyl includes, for example, C1-10 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl), etc. Among others , preferred is C1-4 acyl [e.g., C1-4 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl etc.].
Preferred examples of the substituents of the hydrocarbon group which may be substituted for R1 include (1) nitro, (2) amino which may be substituted by C1-10alkyl, C1-10 acyl (C1-10 alkanoyl) or C1-6 alkoxy-carbonyl, (3) hydroxy which may be substituted by C1-6 alkyl, C1-4 acyl (C1-4 alkanoyl), C1-30 alkoxy-carbonyl, C1-6 alkylcarbonyl, C1-6 cycloalkyl-oxycarbonyl or trifluorosulfonyl, (4) a group of the formula: xe2x80x94S(O) n xe2x80x94R12 wherein n represents an integer of 0 to 2, and R12 represents hydrogen or C1-20 hydrocarbon group (preferably C1-6 alkyl), and so forth.
R1 is preferably (1) C1-20 hydrocarbon group (preferably C1-6 alkyl) and (2) C1-20 hydrocarbon group (preferably C1-6 alkyl) substituted by amino which may be substituted by C1-6 alkyl, C7-19 aralkyl (C6-14 aryl-C1-6 alkyl), etc. More preferably R1 is (1) C1-6 alkyl and (2) Nxe2x80x94C7-19 aralkyl-Nxe2x80x94C1-6 alkylamino-C1-6 alkyl (Nxe2x80x94C6-14 aryl-C1-5 alkyl-Nxe2x80x94C1-6 alkylamino-C1-6 alkyl) etc.
Preferred examples of the substituents of the hydrocarbon group which may be substituted for R2 include (1) nitro, (2) halogen, (3) a group of the formula: xe2x80x94S(O) n xe2x80x94R12 wherein n represents an integer of 0 to 2, and R12 represents hydrogen or C1-20 hydrocarbon group (preferably C1-6 alkyl), (4) carbamoyl, (5) a group through carbonyl (e.g., C1-6 alkoxy-carbonyl, etc.), and so forth.
R2 is preferably C1-20 hydrocarbon group (e.g., C6-14 aryl). More preferably R2 is (1) C6-14 aryl, (2) C1-8 alkanoyl-amino-C6-14 aryl, (3) C2-10 alkenyl-C1-6 alkoxy-C6-14 aryl, and so forth.
In the formulae, the halogen for X includes fluoro, chloro, bromo and iodo. Among others, preferred is bromo.
R3 is preferably C1-20 hydrocarbon group (e.g., C1-6 alkyl, C2-6 alkenyl, C6-14 aryl, etc.). More preferred is methyl, isopropyl or phenyl.
R4 is preferably C1-20 hydrocarbon group (e.g., C1-6 alkyl, C2-6 alkenyl, C6-14 aryl, etc.). More preferred is ethyl, etc.
R5 is preferably hydrogen.
R6 represents hydrogen, sodium, potassium or a hydrocarbon group. R6 is preferably C1-20 hydrocarbon group (e.g., C1-6 alkyl, C2-6 alkenyl, C6-14 aryl, etc.).
The production of the present invention is as follows. 
wherein R1xe2x80x2 and R2xe2x80x2 each represents a hydrocarbon group which may be substituted, R1xe2x80x3 and R2xe2x80x3 form, taken together with adjacent two carbon atoms, a 5- to 7-membered ring which may be substituted, and other symbols are as defined above.
The above xe2x80x9chydrocarbon group which may be substitutedxe2x80x9d and the xe2x80x9c5- to 7-membered ring which may be substitutedxe2x80x9d are as defined above, respectively. The compound of the above formula (VIIIxe2x80x2) is sometimes refereed as compound (VIIIxe2x80x2). The compound of the above formula (VIIIxe2x80x2xe2x80x2) is sometimes refereed as compound (VIIIxe2x80x3).
1. Cyclization is Carried Out as Follows.
(1) Firstly, thiophene compound (II) is reacted with compound (III) to produce compound (IV).
In this reaction, about 1 to 5 mol, preferably 1 to 2 mol of compound (III) is used relative to one mol of compound (II).
In this reaction, there is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Such solvent includes, for example, hydrocarbons (e.g., n-hexane, benzene, toluene, xyxlene, etc.), halogenated hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc.), ethers (e.g., diethylether, diisopropylether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), nitrites (e.g., acetonitrile, etc.), esters (e.g., ethyl acetate, etc.), amides (e.g., N,N-dimethylformamide, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), sulfoxides (e.g., dimethylsulfoxide, etc.) and mixtures of those solvents. This reaction is preferably carried out in the presence of an acid to promote this reaction. The acid includes an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. The amount of the acid is about 0 to 5 equivalents, preferably about 0.01 to 0.5 equivalents relative to one mol of compound (II).
The reaction temperature is about 0 to 180xc2x0 C., preferably about 10 to 50xc2x0 C. The reaction time is about 10 minutes to 24 hours, preferably about 1 to 2 hours.
Compound (II) is produced by the per se known method, for example, the method described in K. Gewald, et. al., Chem. Ber. 99, 94, 1966, or analogue methods thereto. Compound (III) is produced by the per se known method, for example, methods described in J. Dabrowski, et. al., Bull. Chem. Soc. Jpn. 48 1310, 1975, or U. Lienhard, et. al., Helv. Chim. Acta, 61, 1609, 1978, or analogous methods thereto. (2) The reaction in which compound (IV) is subjected to cyclization to produce compound (V) is carried out by heating compound (IV).
The reaction is carried out by heating compound (IV) at about 100 to 300xc2x0 C., preferably about 200 to 280xc2x0 C., for about 30 minutes to 30 hours, preferably about 1 to 6 hours, with distilling off an alcohol (e.g., ethanol, etc.) which is produced during the reaction.
This reaction may be carried out without a solvent or in the presence of a solvent. When a solvent is used, preferred is a solvent which does not interfere with the cyclization and has a high boiling point (e.g., a solvent having b.p. 100xc2x0 C. or more). Such solvent includes, for example, diethylene glycol dibutyl ether, diphenyl ether, diethyl phthalate, etc.
2. A Compound of the Formula: 
wherein each symbol is as defined above, can be produced [hereinafter, sometimes referred to as compound (VIII)] by introducing a difluorophenyl-methyl group to the 7-position of compound (V).
In this reaction about 1 to 2 mol. preferably about 1 to 1.2 mol of halogenated difluorophenyl-methyl compound is added relative to one mol of compound (V).
This reaction is advantageously carried out in the presence of a base. Such base includes, for example, an inorganic base such as an alkali metal or alkaline earth metal hydrogencarbonate (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), an alkali metal or alkaline earth metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), an alkali metal or alkaline earth metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.) and an organic base such as an alkylamine (e.g., triethylamine, diisopropylethylamine, etc.), and so forth. The amount of the base to be used is about 1 to 2 mol relative to one mol of compound (V).
In this reaction, there is no particular limitation on the kind of solvent that can be used unless the reaction is interfered with. Among others, preferred are ethers (e.g., diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), nitrites (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide etc.), ketones (e.g., acetone, methyl ethylketone, etc.), etc.
The reaction temperature is about 0 to 100xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 2 to 3 hours.
Salts of compounds used in these reactions and salts of compounds obtained in these reactions (hereinafter, referred to as xe2x80x9ccompound of the present inventionxe2x80x9d) are preferably physiologically acceptable acid addition salts. Such salts include, for example, salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid hydrobromic acid, sulfuric acid, etc.), saltswithorganic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.), and so forth. For example, when a compound of the present invention has an acidic group such as carboxylic acid, it may form a physiologically acceptable salt with an inorganic base (e.g., alkali metals or alkaline earth metals such as sodium, potassium, calcium and magnesium; ammonia; etc.) or an organic base (e.g., tri-C1-3 alkylamine such as triethylamine, etc.). The compound in free form can be converted to a salt and the one in salt form can be converted to a free form by per se known methods or analogous thereto.
In JP-A-8-295693 (WO 95/28405), 2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine is shown merely as an amorphous. In the present invention, 2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine can be obtained as a stable crystalline salt according to, for example, the following examples. The above crystalline salts include physiologically acceptable acid addition salts such as salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.), salts withorganic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.), and so forth. Preferably, the crystalline salts are salts with hydrochloric acid, methanesulfonic acid, dibasic acid (e.g., fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid, etc.), or tribasic acid (e.g., 1,2,3-propanetricarboxylic acid, etc.), more preferably, salts with dibasic acid (preferably, fumaric acid, malonic acid, succinic acid, malic acid, etc.).
Crystalline salt of 2-(4-aminophenyl)-3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-5-isobutyryl-4-oxothieno[2,3-b]pyridine, of the present invention is stable so that it can be easily isolated and purified and it can be preserved in stable condition for long term.
When the compound has a double bond, and there exist stereoisomers of Z- or E-form, Z-form, E-form and their mixture may be used.
When the compound has a chiral carbon atom, and there exist stereoisomers, each of them and their mixture are within the scope of the present invention.
When the compound of the present invention or a salt thereof is an optically active compound, it can be resolved into the d- and l -forms by the conventional optical resolution techniques.
Thus obtained compound or its salt may be isolated and purified by ordinary means of separation such as solvent extraction, concentration under reduced pressure, crystallization, recrystallization, distillation chromatography, and the like.
The compound obtained in the present invention or a salt thereof can be submitted to the next reaction either as the reaction mixture or after partial purification.
Compound (VIII) obtained by the methods of the present invention or a salt thereof can be used as a synthetic intermediate for production of thienopyridine derivatives having GnRH antagonistic activity or compounds containing such derivative as partial structure [hereinafter, sometimes referred to as compound (IX)].
Thienopyridine derivatives having GnRH antagonistic activity [hereinafter, referred to as compound (IXxe2x80x2)] or their salts can be produced from thienopyridine derivatives in compound (VIII) [hereinafter, referred to as compound (VIIIxe2x80x2)] or their salts, according to methods described in JP-A-8-295693 (WO 95/28405) or analogous methods thereto.
Since a compound of Formula (VIII) wherein a ring formed by R10 and R2 together with adjacent two carbon atoms has a substituent [hereinafter, referred to as compound (VIIIxe2x80x3)] or its salt can be used in a manner similar to that described in JP-A-8-295693 (WO 95/28405) by converting the substituent in said compound or by further introducing a substituent thereinto to produce a GnRH antagonistic compound [sometimes abbreviated as compound (IXxe2x80x3), which means a compound having as a part a thienopyridine derivative described above] or its salt, compound (VIIIxe2x80x3) or its salt can be used as an intermediate for producing compound (IXxe2x80x3) or its salt.
Since compound (IX) or its salt has a GnRH antagonistic activity with a low toxicity, it can be used as a GnRH antagonist in a manner similar to that described in JP-A-8-295693 (WO 95/28405).
A thienopyridine derivative described above (compound (IX) or its salt) produced from a compound obtained by a method of the invention has an excellent GnRH antagonistic activity and has a low toxicity. Accordingly, said thienopyridine derivative suppresses the secretion of a gonadotropin through its GnRH receptor antagonism in a mammal (for example, human, monkey, cattle, horse, dog, cat, rabbit, rat, mouse, etc.) to provide a control of the blood levels of sex hormones, due to which it can safely be employed in the prophylaxis and the treatment of a androgenic hormone- or estrogenic hormone-dependent disease or a disease attributable to the hypersecretion of such hormone.
For example, said thienopyridine derivative is useful in the prophylaxis and the treatment of a sex hormone-dependent cancer (e.g., prostatic cancer, uterine cancer, mammary cancer, pituitary tumor, etc.) as well as prostatomegaly, hysteromyoma, endometriosis, precocious puberty, amenorrhea, premenstrual syndrome, multilocular ovary syndrome, acne and the like. It is useful also in the preoperative treatment before a surgery of any disease listed above as well as in the postoperative prevention of a recurrence. Said thienopyridine derivative is useful also in controlling the reproduction in males and females (e.g., pregnancy regulator, menstrual period regulator, etc.). A thienopyridine derivative may be used also as a contraceptive in males and females or as an ovulation-promoting agent in females. Said thienopyridine derivative may be used in the treatment of a sterility by utilizing the rebound effect thereof after discontinuation.
Said thienopyridine derivative of the invention is useful also in a field of stockbreeding for controlling an estrus of an animal, improving the texture of a meat, or promoting the growth of an animal. Said thienopyridine derivative is useful also as a opposition-promoting agent in fish.